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PSYCHOPHARMACOLOGY
2019 NEI Congress Highlights: What to Do When D2 Isn't Enough
November 9, 2019   

At 2019 NEI Congress, Dr. Andrew Cutler presented on novel antipsychotic mechanisms. Schizophrenia has been primarily associated wtih dopamine dysfunction, and all effective treatments directly target the dopamine D2 receptor. However, the core pathophysiology of schizophrenia may also involve dysfunction of multiple other neurotransmitter systems, including glutamater, serotonin, acetylcholine, and gamma-aminobutyric acid (GABA). To that end, novel treatment development is focusing on targets beyond dopamine (Tables 1 and 2).

Table 1. Beyond the D2 Hypothesis: Novel Treatment Targets for Schizophrenia
Hypothesis Target Strategy
Glutamate NMDA, AMPA, or metabotropic receptors Improve negative and cognitive symptoms
Serotonin 5HT1A agonists, 5HT2C antagonists and agonists, 5HT3 antagonists, 5HT6 and 5HT7 antagonists, 5HT reuptake inhibitors Reduce EPS
Improve negative, mood and cognitive symptoms
Potential treatment for different phases of the illness
Acetylcholine a-7 nicotinic and M1 muscarinic agonists and positive allosteric modulators Nicotinic agonists for cognitive symptoms
Muscarinic agonists for positive symptoms
GABA Selective GABA-A agonists, GABA-B antagonists, and allosteric modulators at GABA-A receptor subtypes Augmentation of psychosis treatment
Inflammation Cytokines Possibly the early period of psychosis
Phosphodiesterase (PDE) PDE-10A inhibitor Activates cAMP/PKA signaling, leading to potentiation of D1 receptor signaling, and inhibition of D2 receptor signaling
NMDA: N-methyl-D-aspartate; AMPA: alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid; 5HT: 5-hydroxytryptamine (serotonin); GABA: gamma-aminobutyric acid.


Table 2. Agents in Phase III Clinical Trials
Agent Mechanism of action Potential indication
Lumateperone (ITI-007) 5HT2A antagonist, 5HT transport inhibitor, presynaptic, D2 partial agonist, postsynaptic D2 antagonist, D1-regulated NMDA and AMPA agonist Schizophrenia, bipolar depression, agitation in patients with dementia, neuropsychiatric/neurodegenerative diseases
RO5263397 (monotherapy) Trace amine-associated redeptor (TAAR) 1 agonist Schizophrenia
SEP-363856 (monotherapy) TAAR1 agonist Schizophrenia
Roluperidone (MIN-101) (monotherapy) 5HT2A antagonist, sigma 2 antagonist, alpha1-adrenergic antagonist Schizophrenia
LuAF-35700 (monotherapy) D1 antagonist (>D2 antagonist), 5HT2A antagonist, 5HT6 occupancy
Pimavanserin (add-on) 5HT2A inverse agonist Schizophrenia, major depressive disorder, Parkinson’s psychosis, psychosis in Alzheimer’s disease
Paliperidone Palmitate 6-monthly formulation (monotherapy) 5HT2A antagonist, D2 antagonist Schizophrenia
Risperidone extended release subcutaneous injection (TV46000) (monotherapy) 5HT2A antagonist, D2 antagonist Schizophrenia
Risperidone ISM ® (Doriafi) (monotherapy) 5HT2A antagonist, D2 antagonist Schizophrenia
Samidorphan/Olanzapine (ALKS3831) (monotherapy) mu-opioid antagonist/5HT2A antagonist, D2 antagonist Olanzapine-induced weight gain + schizophrenia
NMDA: N-methyl-D-aspartate; AMPA: alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid; 5HT: 5-hydroxytryptamine (serotonin).

Of course, not all treatment for schizophrenia is pharmacological. In his presentation, Dr. Cutler also distilled the data for transcranial magnetic stimulation (TMS) for auditory hallucinations and cognitive impairment, as well as two approaches (training or strategy) for cognitive remediation therapy.

Reference:
Andrew J. Cutler, MD (November, 2019). I Blocked D2 and All I Got Was This Lousy Side Effect: What to Do When D2 Isn’t Enough. Presented at 2019 NEI Congress, Colorado Springs, CO.

Stay tuned for the Encore Presentation (releasing December 2019):

I Blocked D2 and All I Got Was This Lousy Side Effect: What to Do When D2 Isn’t Enough

For more information on novel antipsychotic mechanisms:

Keeping Up With the Therapeutic Advances in Schizophrenia: A Review of Novel and Emerging Pharmacological Entities